Neurokinin-1 Receptor Antagonists
The potential use of NK-1 receptor antagonists as antiemetics became apparent when the role of substance P in the peripheral and CNS was recognized in the emetic stimulus pathway. Aprepitant, the first NK-1 receptor antagonist available, has been studied for the prevention of CINV caused by moderately and highly emetogenic chemotherapy. Aprepitant is usually given as a 3-day oral regimen 125 mg on day 1 and 80 mg on days 2 and 3. Early trials determined that aprepitant could not replace a serotonin antagonist, but that it would be used best in conjunction with corticosteroids and a serotonin antagonist.
Aprepitant was studied in two phase III trials for the prevention of CINV with highly emetogenic cisplatin-based chemotherapy.35,36 In both of these trials, aprepitant (or placebo) was added to a standard antiemetic regimen of ondansetron on day 1 and dexamethasone on days 1 through 4. The patients treated with aprepitant showed improved complete response rates (no emesis, and no use of rescue medications) by about 20%, in both the acute and delayed phases. In a recent reanalysis,37 investigators found that the aprepitant-containing regimens were more effective in women than in men, which is fortunate because women have more acute and delayed symptoms than men.
Aprepitant was also studied in the prevention of CINV caused by moderately emetogenic chemotherapy.38 Patients in the treatment arm were given aprepitant, ondansetron, and dexamethasone on day 1 plus aprepitant on days 2 and 3. The patients in the control arm were given ondansetron and dexamethasone on day 1, plus ondansetron on days 2 and 3. The rate of complete response (no emesis and no use of rescue medications) was higher in the aprepitant arm in both the acute and delayed phases. Dexamethasone, however, is one of the most effective agents for delayed CINV symptoms and it was not used in either arm for the delayed phase. In essence, aprepitant was not compared with the standard of care for the delayed phase. The results may not have been significant if a proper comparator had been used.
The effects of aprepitant seem to be maintained over four cycles of chemotherapy in patients receiving moderately emetogenic chemotherapy.39 The addition of aprepitant to the antiemetic regimen on cycle 2 (even when it was omitted from cycle 1) also seems to improve control of CINV symptoms.40,41 For patients who have had inadequate response to an antiemetic regimen that did not include aprepitant, it may be useful to add it in later cycles.
The efficacy of aprepitant for the control of delayed CINV symptoms was confirmed in a trial that included 489 patients comparing a standard aprepitant regimen (aprepitant, ondansetron, and dexamethasone on day 1, followed by aprepitant and dexamethasone on days 2 and 3, and dexamethasone on day 4) to a nonaprepitant regimen (ondansetron and dexamethasone on days 1 through 4) in patients receiving highly emetogenic chemotherapy.42 The aprepitant-containing regimen offered superior control of CINV in the acute, delayed, and overall time periods. The study confirmed that aprepitant is a better choice than a serotonin antagonist during the delayed phase of CINV.
Aprepitant is generally well tolerated with mild side effects, including fatigue, hiccups, headache, and diarrhea.35,36,38,42 The overall adverse effects in standard aprepitant-containing regimens are not appreciably different from regimens without aprepitant.35,36,37,38,42 A potential disadvantage of aprepitant is the unavailability of an IV formulation.
Aprepitant is metabolized by the CYP3A4 enzyme system. It is a moderate inhibitor and inducer of CYP3A4, and an inducer of CYP2C9.11,43,44,45 Consequently, several drugs potentially interact with aprepitant. The most commonly encountered interaction is with the corticosteroids. Aprepitant increases the area under the curve of dexamethasone such that the dexamethasone dose (when used as an antiemetic) should be reduced by about one-half of the usual dose when these drugs are used together.46 The effect is greatest when the corticosteroid is administered orally.11,43,44,45,46,47 When the corticosteroid is also given as part of the antitumor regimen, however, the dose should not be reduced because of concern that the antineoplastic activity might be compromised.14 Aprepitant may also enhance warfarin metabolism by inducing CYP2C9. International normalized ratio (INR) values in patients treated
with warfarin and the standard aprepitant regimen are significantly reduced, especially on day 8 of the chemotherapy cycle.48 The patient's coagulation status after aprepitant administration should be monitored, especially during the 7- to 10-day time period. The dosage of warfarin should be adjusted if the INR is high or low. Several chemotherapy agents (paclitaxel, etoposide, paclitaxel, ifosfamide, irinotecan, imatinib, vinca alkaloids, and others) are metabolized by the CYP3A4 enzyme system and the metabolism of these agents may be altered by aprepitant. Aprepitant was used in clinical trials with some of these agents. Caution is warranted, however, because the clinical relevance of this effect is not known.18 Other drugs that may interact with aprepitant include oral contraceptives, itraconazole, terfenadine, and phenytoin.43,44,47
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A new investigational NK-1 receptor antagonist, casopitant, has been studied for the prevention of CINV symptoms in patients receiving moderately and highly emetogenic chemotherapy in preliminary phase II/III trials using doses of 50 to 150 mg daily.49,50 The initial results suggest that further trials with this agent are warranted
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